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British Journal of Anaesthesia
BJA

Continuous cerebrovascular reactivity monitoring in moderate/severe traumatic brain injury: a narrative review of advances in neurocritical care

Open ArchivePublished:January 23, 2020DOI:https://doi.org/10.1016/j.bja.2019.11.031

      Summary

      Impaired cerebrovascular reactivity in adult moderate and severe traumatic brain injury (TBI) is known to be associated with worse global outcome at 6–12 months. As technology has improved over the past decades, monitoring of cerebrovascular reactivity has shifted from intermittent measures, to experimentally validated continuously updating indices at the bedside. Such advances have led to the exploration of individualised physiologic targets in adult TBI management, such as optimal cerebral perfusion pressure (CPP) values, or CPP limits in which vascular reactivity is relatively intact. These targets have been shown to have a stronger association with outcome compared with existing consensus-based guideline thresholds in severe TBI care. This has sparked ongoing prospective trials of such personalised medicine approaches in adult TBI. In this narrative review paper, we focus on the concept of cerebral autoregulation, proposed mechanisms of control and methods of continuous monitoring used in TBI. We highlight multimodal cranial monitoring approaches for continuous cerebrovascular reactivity assessment, physiologic and neuroimaging correlates, and associations with outcome. Finally, we explore the recent ‘state-of-the-art’ advances in personalised physiologic targets based on continuous cerebrovascular reactivity monitoring, their benefits, and implications for future avenues of research in TBI.

      Keywords

      Cerebrovascular reactivity has emerged as a monitored physiologic parameter of interest in adult critically ill traumatic brain injury (TBI) patients, with support from recent multimodal monitoring (MMM) consensus statements.
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      The International Multidisciplinary Consensus Conference on Multimodality Monitoring in Neurocritical Care: evidentiary tables: a statement for healthcare professionals from the neurocritical care society and the European society of intensive care medicine.
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      Participants in the international multidisciplinary consensus conference on multimodality monitoring. Monitoring of cerebral autoregulation.
      Given the inter-patient heterogeneity in cerebrovascular reactivity after TBI,
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      Sex-related differences and traumatic brain injury.
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      Variants of the endothelial nitric oxide gene and cerebral blood flow after severe traumatic brain injury.
      the association with clinical outcome,
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      Univariate comparison of performance of different cerebrovascular reactivity indices for outcome association in adult TBI: a CENTER-TBI study.
      and the relative lack of good therapies directed at dysfunction,
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      Twenty-five years of intracranial pressure monitoring after severe traumatic brain injury: a retrospective, single-center analysis.
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      Clinical and physiological events that contribute to the success rate of finding ‘optimal’ cerebral perfusion pressure in severe brain trauma patients.
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      Cerebrovascular reactivity is not associated with therapeutic intensity in adult traumatic brain injury: a CENTER-TBI analysis.
      there has emerged the desire and need for tailored therapeutic approaches. Such personalised therapies would require continuous cerebrovascular reactivity monitoring capabilities at the bedside,
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      Participants in the international multidisciplinary consensus conference on multimodality monitoring. Monitoring of cerebral autoregulation.
      ,
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      Visualizing the pressure and time burden of intracranial hypertension in adult and paediatric traumatic brain injury.
      the ability to derive and display patient-specific physiologic metrics in real time,
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      • et al.
      Continuous monitoring of cerebrovascular pressure reactivity allows determination of optimal cerebral perfusion pressure in patients with traumatic brain injury.
      ,
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      Patient-specific thresholds of intracranial pressure in severe traumatic brain injury.
      and the availability of autoregulation modulating therapies.
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      • Piechnik S.K.
      • et al.
      Continuous monitoring of cerebrovascular pressure reactivity allows determination of optimal cerebral perfusion pressure in patients with traumatic brain injury.
      ,
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      Optimal cerebral perfusion pressure in centers with different treatment protocols.
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      Comparison of performance of different optimal cerebral perfusion pressure parameters for outcome prediction in adult TBI: a CENTER-TBI study.
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      • et al.
      Continuous determination of optimal cerebral perfusion pressure in traumatic brain injury.
      Recent improvements in continuous cerebrovascular reactivity monitoring in TBI can facilitate detection and continuous monitoring of individualised autoregulation guided cerebral perfusion pressure (CPP) and intracranial pressure (ICP) targets.
      • Steiner L.A.
      • Czosnyka M.
      • Piechnik S.K.
      • et al.
      Continuous monitoring of cerebrovascular pressure reactivity allows determination of optimal cerebral perfusion pressure in patients with traumatic brain injury.
      ,
      • Lazaridis C.
      • DeSantis S.M.
      • Smielewski P.
      • et al.
      Patient-specific thresholds of intracranial pressure in severe traumatic brain injury.
      ,
      • Aries M.J.H.
      • Czosnyka M.
      • Budohoski K.P.
      • et al.
      Continuous determination of optimal cerebral perfusion pressure in traumatic brain injury.
      Although such individualised targets have been shown to be associated with improved outcomes retrospectively, the benefit of using these targets needs to be proven in prospective interventional randomised control trials. Although such trials would currently focus on manipulations of physiology and outcome improvement, an understanding of the biological basis for dysautoregulation could lead to the development of therapies that restore autoregulatory efficiency. Such understanding could emerge from studies of the molecular and genetic mechanisms involved in cerebral autoregulation in TBI.
      • Zeiler F.A.
      • Thelin E.P.
      • Donnelly J.
      • et al.
      Genetic drivers of cerebral blood flow dysfunction in TBI: a speculative synthesis.
      This could represent a major step towards personalised and precision medicine in moderate and severe TBI care.
      The following review explores continuous cerebrovascular reactivity monitoring in adult TBI, highlighting the background, theories of control, methods of monitoring, clinical literature, the move towards personalised physiologic targets during current neurocritical care management, and future directions of research.

      Defining cerebral autoregulation

       Definition

      Cerebral autoregulation refers to the ability of the cerebral vascular system to maintain relatively constant levels of cerebral blood flow (CBF), despite changes in system MAP or CPP. The concept of cerebral autoregulation was first described by Fog,
      • Fog M.
      The relationship between the blood pressure and the tonic regulation of the pial arteries.
      in controlled CBF assessments in cats, and Lassen
      • Lassen N.A.
      Cerebral blood flow and oxygen consumption in man.
      through observational studies of CBF in humans during different CO2 and MAP manipulations. Both described the static phenomenon of the cerebral vessels innate ability to regulate CBF to a constant level, across different levels in MAP.
      • Fog M.
      The relationship between the blood pressure and the tonic regulation of the pial arteries.
      ,
      • Lassen N.A.
      Cerebral blood flow and oxygen consumption in man.
      Of note, given the technical limitations of the time, such descriptions did not use continuously updating assessments based on slow-wave vasogenic fluctuations, which are now emerging as the main method for continuous beside assessment. Since Fog
      • Fog M.
      The relationship between the blood pressure and the tonic regulation of the pial arteries.
      and Lassen
      • Lassen N.A.
      Cerebral blood flow and oxygen consumption in man.
      , various studies in pre-clinical experimental models
      • Brady K.M.
      • Lee J.K.
      • Kibler K.K.
      • Easley R.B.
      • Koehler R.C.
      • Shaffner D.H.
      Continuous measurement of autoregulation by spontaneous fluctuations in cerebral perfusion pressure: comparison of 3 methods.
      • Zeiler F.A.
      • Donnelly J.
      • Calviello L.
      • et al.
      Validation of pressure reactivity and pulse amplitude indices against the lower limit of autoregulation: Part I. Experimental intra-cranial hypertension.
      • Zeiler F.A.
      • Lee J.K.
      • Smielewski P.
      • Czosnyka M.
      • Brady K.
      Validation of ICP derived cerebrovascular reactivity indices against the lower limit of autoregulation: Part II. Experimental model of arterial hypotension.
      • Nemoto E.M.
      • Snyder J.V.
      • Carroll R.G.
      • Morita H.
      Global ischemia in dogs: cerebrovascular CO2 reactivity and autoregulation.
      • Symon L.
      • Crockard H.A.
      • Dorsch N.W.
      • Branston N.M.
      • Juhasz J.
      Local cerebral blood flow and vascular reactivity in a chronic stable stroke in baboons.
      • Russell R.W.
      The reactivity of the pial circulation of the rabbit to hypercapnia and the effect of vascular occlusion.
      • Jakubowski J.
      • Bell B.A.
      • Symon L.
      • Zawirski M.B.
      • Francis D.M.
      A primate model of subarachnoid hemorrhage: change in regional cerebral blood flow, autoregulation carbon dioxide reactivity, and central conduction time.
      and humans
      • Sorrentino E.
      • Diedler J.
      • Kasprowicz M.
      • et al.
      Critical thresholds for cerebrovascular reactivity after traumatic brain injury.
      ,
      • Zeiler F.A.
      • Ercole A.
      • Cabeleira M.
      • et al.
      Univariate comparison of performance of different cerebrovascular reactivity indices for outcome association in adult TBI: a CENTER-TBI study.
      ,
      • Czosnyka M.
      • Smielewski P.
      • Kirkpatrick P.
      • Laing R.J.
      • Menon D.
      • Pickard J.D.
      Continuous assessment of the cerebral vasomotor reactivity in head injury.
      • Flechet M.
      • Meyfroidt G.
      • Piper I.
      • et al.
      Visualizing cerebrovascular autoregulation insults and their association with outcome in adult and paediatric traumatic brain injury.
      • Depreitere B.
      • Güiza F.
      • Van den Berghe G.
      • et al.
      Can optimal cerebral perfusion pressure in patients with severe traumatic brain injury be calculated based on minute-by-minute data monitoring?.
      • Howells T.
      • Johnson U.
      • McKelvey T.
      • Enblad P.
      An optimal frequency range for assessing the pressure reactivity index in patients with traumatic brain injury.
      • Svedung Wettervik T.
      • Howells T.
      • Enblad P.
      • Lewén A.
      Temporal neurophysiological dynamics in traumatic brain injury: role of pressure reactivity and optimal cerebral perfusion pressure for predicting outcome.
      • Budohoski K.P.
      • Czosnyka M.
      • Kirkpatrick P.J.
      • Smielewski P.
      • Steiner L.A.
      • Pickard J.D.
      Clinical relevance of cerebral autoregulation following subarachnoid haemorrhage.
      have described the concept of cerebral autoregulation, and outline different methods of assessment.
      • Zeiler F.A.
      • Donnelly J.
      • Calviello L.
      • Smielewski P.
      • Menon D.K.
      • Czosnyka M.
      Pressure autoregulation measurement techniques in adult traumatic brain injury: Part II. A scoping review of continuous methods.
      • Zeiler F.A.
      • Donnelly J.
      • Calviello L.
      • Menon D.K.
      • Smielewski P.
      • Czosnyka M.
      Pressure autoregulation measurement techniques in adult traumatic brain injury: Part I. A scoping review of intermittent/semi-intermittent methods.
      • Klein S.P.
      • Depreitere B.
      • Meyfroidt G.
      How I monitor cerebral autoregulation.
      Fig. 1 shows our conceptual understanding of cerebral autoregulation and the relationship between CBF and MAP, during both healthy and various diseased states related to TBI.
      Fig 1
      Fig 1Diagrammatic representation of cerebral autoregulatory curve and consequences of selected Pathology. (a) The classic ‘Lassen’ curve showing the relationship between CPP and CBF (black line). The grey line is suggested to be the autoregulation curve in a cohort of patients with long-standing hypertension. The LLA and the ULA are shifted to the right. In addition, the plateau might decrease compared with intact cerebral autoregulation cohort. (b) Compared with the classic ‘Lassen’ autoregulation curve (black line), the autoregulation curve of severe TBI patients with generalised cerebral edema might look like the grey curve. The LLA is shifted to the right and the ULA is shifted to the left resulting in a smaller plateau. In addition, the slopes of the different parts are likely steeper and the plateau has shifted downwards indicating a lower absolute perfusion state. (c) Compared with the classic ‘Lassen’ curve (black line) totally impaired cerebral autoregulation can be represented by a steep (grey) line. No autoregulation plateau is present and CBF is following changes in CPP passively. CBF, cerebral blood flow; CPP, cerebral perfusion pressure; LLA, lower limit of autoregulation; TBI, traumatic brain injury; ULA, upper limit of autoregulation.

       Classic theories of cerebral blood flow control

      In general, the brain arterial bed can be divided to conducting and regulating arteries/arterioles. Small precapillary arterioles are believed to be the key vessels involved in cerebral autoregulation, measuring up to a few hundred microns in diameter, and representing the main site where active vasoconstriction and dilatation takes place,
      • Hundley W.G.
      • Renaldo G.J.
      • Levasseur J.E.
      • Kontos H.A.
      Vasomotion in cerebral microcirculation of awake rabbits.
      • Halpern W.
      • Osol G.
      Influence of transmural pressure of myogenic responses of isolated cerebral arteries of the rat.
      • Auer L.M.
      • Ishiyama N.
      • Pucher R.
      Cerebrovascular response to intracranial hypertension.
      typically occurring in the slow-wave vasogenic frequency range of 0.05–0.005 Hz.
      • Howells T.
      • Johnson U.
      • McKelvey T.
      • Enblad P.
      An optimal frequency range for assessing the pressure reactivity index in patients with traumatic brain injury.
      ,
      • Fraser C.D.
      • Brady K.M.
      • Rhee C.J.
      • et al.
      The frequency response of cerebral autoregulation.
      The mechanisms involved in the control of cerebrovascular tone, and thus vasoregulatory capacity, have been detailed in various other publications.
      • Zeiler F.A.
      • Thelin E.P.
      • Donnelly J.
      • et al.
      Genetic drivers of cerebral blood flow dysfunction in TBI: a speculative synthesis.
      ,
      • Budohoski K.P.
      • Czosnyka M.
      • Kirkpatrick P.J.
      • Smielewski P.
      • Steiner L.A.
      • Pickard J.D.
      Clinical relevance of cerebral autoregulation following subarachnoid haemorrhage.
      ,
      • Winn H.
      Youmans neurological surgery.
      • Armstead W.M.
      Cerebral blood flow autoregulation and dysautoregulation.
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      • Csiszar A.
      • Prodan C.I.
      Cerebral microhemorrhages: mechanisms, consequences, and prevention.
      • Kisler K.
      • Nelson A.R.
      • Montagne A.
      • Zlokovic B.V.
      Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease.
      Table 1 provides an account of the various theorised mechanisms involved in CBF control in humans. In general, four main classical mechanisms
      • Zeiler F.A.
      • Thelin E.P.
      • Donnelly J.
      • et al.
      Genetic drivers of cerebral blood flow dysfunction in TBI: a speculative synthesis.
      ,
      • Winn H.
      Youmans neurological surgery.
      ,
      • Armstead W.M.
      Cerebral blood flow autoregulation and dysautoregulation.
      of CBF control have emerged: myogenic, endothelial, neurogenic, and metabolic. The myogenic mechanism is predicated on the notion that slow changes in flow induce shear stress and vascular smooth muscle stretch lead to reflex alterations in smooth muscle tone, and thus vessel diameter, controlling CBF.
      • Izzard A.S.
      • Heagerty A.M.
      Myogenic properties of brain and cardiac vessels and their relation to disease.
      • Gebremedhin D.
      • Gopalakrishnan S.
      • Harder D.R.
      Endogenous events modulating myogenic regulation of cerebrovascular function.
      • Koller A.
      • Toth P.
      Contribution of flow-dependent vasomotor mechanisms to the autoregulation of cerebral blood flow.
      • Faraci F.M.
      • Baumbach G.L.
      • Heistad D.D.
      Myogenic mechanisms in the cerebral circulation.
      This theory relies on smooth muscle stretch receptors and calcium based sarcolemma changes leading to variations in smooth muscle function. The endothelial mechanism revolves around shear stress operating on the endothelial lining of cerebral vessels, leading to induced changes in vascular mediator expression, including but not limited to factors such as nitric oxide synthase (NOS) and endothelin (ET).
      • Faraci F.M.
      • Heistad D.D.
      Regulation of the cerebral circulation: role of endothelium and potassium channels.
      • Hall C.N.
      • Reynell C.
      • Gesslein B.
      • et al.
      Capillary pericytes regulate cerebral blood flow in health and disease.
      • Brian J.E.
      • Faraci F.M.
      • Heistad D.D.
      Recent insights into the regulation of cerebral circulation.
      These mediators lead to change in cerebrovascular tone, and thus CBF. The neurogenic mechanisms involve the direct neural input for vasomotor control, as mediated by various neurotransmitters such as adrenergic/noradrenergic, dopaminergic, serotonergic, and cholinergic based transmitters.
      • Zeiler F.A.
      • Thelin E.P.
      • Donnelly J.
      • et al.
      Genetic drivers of cerebral blood flow dysfunction in TBI: a speculative synthesis.
      ,
      • Lavinio A.
      • Ene-Iordache B.
      • Nodari I.
      • et al.
      Cerebrovascular reactivity and autonomic drive following traumatic brain injury.
      • Perkes I.
      • Baguley I.J.
      • Nott M.T.
      • Menon D.K.
      A review of paroxysmal sympathetic hyperactivity after acquired brain injury.
      • Sykora M.
      • Czosnyka M.
      • Liu X.
      • et al.
      Autonomic impairment in severe traumatic brain injury: a multimodal neuromonitoring study.
      • Palmer G.C.
      Neurochemical coupled actions of transmitters in the microvasculature of the brain.
      • Nakada T.
      The molecular mechanisms of neural flow coupling: a new concept.
      It is postulated that through various synapses of the nervi vasorum, such as direct sympathetic and parasympathetic inputs, vascular tone may be quickly mediated in response to slow changes in driving pressure, leading to control of CBF. Finally, the metabolic mechanism suggests that changes in local metabolite concentrations matched to CBF lead to proportional smooth muscle response.
      • Palmer G.C.
      Neurochemical coupled actions of transmitters in the microvasculature of the brain.
      • Nakada T.
      The molecular mechanisms of neural flow coupling: a new concept.
      • Terashvili M.
      • Pratt P.F.
      • Gebremedhin D.
      • Narayanan J.
      • Harder D.R.
      Reactive oxygen species cerebral autoregulation in health and disease.
      • Murkin J.M.
      Cerebral autoregulation: the role of CO2 in metabolic homeostasis.
      However, the time frame for metabolic changes being the sole regulator of cerebral vascular tone is not in keeping with the rapidity of blood vessel response to changes in driving pressure. Fig. 2 provides a diagrammatic representation of the main CBF control mechanisms, both classical and emerging.
      Table 1Classical theories of cerebral blood flow control. CBF, cerebral blood flow; NT, neurotransmitter. *Lactate and pyruvate are by-products of metabolism known to be associated with impaired cerebral autoregulation in adult TBI. Causality is uncertain, as these may modulate the pH of the microenvironment dictating downstream changes in vascular tone, or may be purely a marker of disease severity.
      Classical theory of controlSummary of mechanismHypothesised main playersLimitations of theory
      MyogenicTransmural pressure stretch of the cerebral vessels stimulates tunica media smooth muscle contraction to regulate flow.Calcium channels

      Renin–angiotensin system
      Limited to ‘reflex’ mediated control of vascular tone in response to changes in CBF. Unlikely to occur in isolation.
      EndothelialEndothelial shear stress experienced during changes in perfusion pressure and CBF lead to release mediators which impact smooth muscle tone.Endothelin

      Nitric oxide

      Adenosine

      Eicosanoids and prostaglandins
      Does not account for known stretch mediated smooth muscle response seen in cerebral vessels.
      NeurotransmitterDirect neural modulation of vascular tone via vasoactive neurotransmitters (NTs).Adrenergic NTs

      Noradrenergic NTs

      Dopaminergic NTs

      Serotonergic NTs
      Unlikely occurs in isolation. Does not account for known myogenic and endothelial response, which can occur independently of neural input.
      MetabolicBy-products of metabolism dictate smooth muscle tone and CBF which leads to CBF/metabolism couplingLactate/pyruvate*

      Adenosine

      Free radicals
      Timeline required for build-up of metabolic by-products is not in keeping with speed of autoregulatory response.
      Fig 2
      Fig 2Theorised mechanisms of CBF and cerebral autoregulation control. (a) Myogenic theory—depicting stretch of smooth muscle related to CBF, and reflex vasoconstriction. (b) Endothelial theory—depicting shear stress of CBF leading to endothelial mediated release of various vasoactive molecules which impact smooth muscle tone. (c) Neurotransmitter theory—depicting neural input into arteriole vascular tone which may be mediated by various NTs. (d) Metabolic theory—depicting mitochondria and highlights intimate role of oxidative metabolism on cellular function, with impaired metabolism potentially leading to altered vascular tone. Note: other potential mediators are listed in upper left dialogue box in the figure. Ad, adenosine; BBB, blood–brain barrier; CBF, cerebral blood flow; CSD, cortical spreading depression; En, endothelial cell; ET, endothelin; Mt, mitochondria; N, neurone; NO, nitric oxide; NT, neurotransmitter; PG, prostaglandins; Sm, smooth muscle; TBI, traumatic brain injury.
      Aside from the classical ‘mechanical’ theories of CBF control, emerging literature suggests the role of other processes in the development of impaired vascular reactivity. Recently, the role for inflammatory cytokines,
      • Zeiler F.A.
      • Thelin E.P.
      • Donnelly J.
      • et al.
      Genetic drivers of cerebral blood flow dysfunction in TBI: a speculative synthesis.
      ,
      • Thelin E.P.
      • Tajsic T.
      • Zeiler F.A.
      • et al.
      Monitoring the neuroinflammatory response following acute brain injury.
      • Helmy A.
      • Carpenter K.L.H.
      • Menon D.K.
      • Pickard J.D.
      • Hutchinson P.J.A.
      The cytokine response to human traumatic brain injury: temporal profiles and evidence for cerebral parenchymal production.
      • Zeiler F.A.
      • McFadyen C.
      • Newcombe V.
      • et al.
      Genetic influences on patient oriented outcomes in TBI: a living systematic review of non-APOE single nucleotide polymorphisms.
      mediators of blood–brain barrier (BBB) dysfunction,
      • Zeiler F.A.
      • Thelin E.P.
      • Donnelly J.
      • et al.
      Genetic drivers of cerebral blood flow dysfunction in TBI: a speculative synthesis.
      ,
      • Zeiler F.A.
      • McFadyen C.
      • Newcombe V.
      • et al.
      Genetic influences on patient oriented outcomes in TBI: a living systematic review of non-APOE single nucleotide polymorphisms.
      • Roberts D.J.
      • Jenne C.N.
      • Léger C.
      • et al.
      Association between the cerebral inflammatory and matrix metalloproteinase responses after severe traumatic brain injury in humans.
      • Roberts D.J.
      • Jenne C.N.
      • Léger C.
      • et al.
      A prospective evaluation of the temporal matrix metalloproteinase response after severe traumatic brain injury in humans.
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      • Hutchinson P.J.A.
      Matrix metalloproteinase expression in contusional traumatic brain injury: a paired microdialysis study.
      • Cousar J.L.
      • Conley Y.P.
      • Willyerd F.A.
      • et al.
      Influence of ATP-binding cassette polymorphisms on neurological outcome after traumatic brain injury.
      • Jha R.M.
      • Puccio A.M.
      • Okonkwo D.O.
      • et al.
      ABCC8 single nucleotide polymorphisms are associated with cerebral edema in severe TBI.
      • Dardiotis E.
      • Paterakis K.
      • Tsivgoulis G.
      • et al.
      AQP4 tag single nucleotide polymorphisms in patients with traumatic brain injury.
      autonomic nervous system,
      • Lavinio A.
      • Ene-Iordache B.
      • Nodari I.
      • et al.
      Cerebrovascular reactivity and autonomic drive following traumatic brain injury.
      ,
      • Sykora M.
      • Czosnyka M.
      • Liu X.
      • et al.
      Autonomic impairment in severe traumatic brain injury: a multimodal neuromonitoring study.
      and cortical spreading depression (CSD)
      • Hartings J.A.
      • Wilson J.A.
      • Hinzman J.M.
      • et al.
      Spreading depression in continuous electroencephalography of brain trauma.
      • Toth P.
      • Szarka N.
      • Farkas E.
      • et al.
      Traumatic brain injury-induced autoregulatory dysfunction and spreading depression-related neurovascular uncoupling: pathomechanisms, perspectives, and therapeutic implications.
      • Ayata C.
      • Lauritzen M.
      Spreading depression, spreading depolarizations, and the cerebral vasculature.
      have all been raised as potential players in the impaired vascular reactivity seen after TBI. These aspects are beyond the scope of this review, but are touched upon briefly, with references, in Appendix A of the online Supplementary material.

      Methods of monitoring autoregulation in traumatic brain injury

      Several approaches have been used for the quantitative assessment of cerebral autoregulation in TBI.
      • Zeiler F.A.
      • Donnelly J.
      • Calviello L.
      • Smielewski P.
      • Menon D.K.
      • Czosnyka M.
      Pressure autoregulation measurement techniques in adult traumatic brain injury: Part II. A scoping review of continuous methods.
      • Zeiler F.A.
      • Donnelly J.
      • Calviello L.
      • Menon D.K.
      • Smielewski P.
      • Czosnyka M.
      Pressure autoregulation measurement techniques in adult traumatic brain injury: Part I. A scoping review of intermittent/semi-intermittent methods.
      • Klein S.P.
      • Depreitere B.
      • Meyfroidt G.
      How I monitor cerebral autoregulation.
      These methods have been categorised in various ways according to the physiological signals used to derive autoregulatory metrics, the monitoring techniques used to detect these, and the temporal and spatial resolution of the metrics that are derived. The nomenclature system in the literature organises autoregulation measurements into those which are (1) intermittent in nature (imaging based metrics)
      • Zeiler F.A.
      • Donnelly J.
      • Calviello L.
      • Menon D.K.
      • Smielewski P.
      • Czosnyka M.
      Pressure autoregulation measurement techniques in adult traumatic brain injury: Part I. A scoping review of intermittent/semi-intermittent methods.
      and (2) those that are robust enough to be applied continuously (ICP or near-infrared spectroscopy [NIRS]).
      • Zeiler F.A.
      • Donnelly J.
      • Calviello L.
      • Smielewski P.
      • Menon D.K.
      • Czosnyka M.
      Pressure autoregulation measurement techniques in adult traumatic brain injury: Part II. A scoping review of continuous methods.
      ,
      • Klein S.P.
      • Depreitere B.
      • Meyfroidt G.
      How I monitor cerebral autoregulation.
      As intermittent techniques are of limited use in autoregulation guided treatment currently, they will not be covered in this review.
      More information on these techniques can be found in Appendix B of the online Supplementary material and the referenced literature.
      For the purpose of overviewing the different techniques, we will focus on those currently used in adult TBI for the continuous assessment of pressure based autoregulatory capacity.

       Continuous autoregulation monitoring

      Continuous measures of cerebral autoregulation/cerebrovascular reactivity are seen as the desired method for cerebral monitoring in critically ill TBI patients. Various simple input–output methods exist, including frequency and time domain based continuous metrics. However, the most commonly described and used methodologies in adult TBI involve time domain based assessments of the relationship between spontaneous slow-wave fluctuations in a continuously measured surrogate of cerebral blood volume (CBV) or CBF as output variables, and a driving pressure for flow as and input variable (MAP or CPP).
      • Zeiler F.A.
      • Donnelly J.
      • Calviello L.
      • Smielewski P.
      • Menon D.K.
      • Czosnyka M.
      Pressure autoregulation measurement techniques in adult traumatic brain injury: Part II. A scoping review of continuous methods.
      The slow-wave vasogenic frequency range of 0.05–0.005 Hz has been identified as the frequency range for cerebrovascular responses related to changes in MAP.
      • Howells T.
      • Johnson U.
      • McKelvey T.
      • Enblad P.
      An optimal frequency range for assessing the pressure reactivity index in patients with traumatic brain injury.
      ,
      • Svedung Wettervik T.
      • Howells T.
      • Enblad P.
      • Lewén A.
      Temporal neurophysiological dynamics in traumatic brain injury: role of pressure reactivity and optimal cerebral perfusion pressure for predicting outcome.
      ,
      • Fraser C.D.
      • Brady K.M.
      • Rhee C.J.
      • et al.
      The frequency response of cerebral autoregulation.
      In order to assess cerebrovascular reactivity from raw signals, the following general time domain process is followed.
      • Czosnyka M.
      • Smielewski P.
      • Kirkpatrick P.
      • Laing R.J.
      • Menon D.
      • Pickard J.D.
      Continuous assessment of the cerebral vasomotor reactivity in head injury.
      ,
      • Zeiler F.A.
      • Donnelly J.
      • Calviello L.
      • Smielewski P.
      • Menon D.K.
      • Czosnyka M.
      Pressure autoregulation measurement techniques in adult traumatic brain injury: Part II. A scoping review of continuous methods.
      First, both the continuous surrogate measures of CBV/CBF and MAP/CPP are captured from bedside monitors at typically 50 Hz or higher frequency. Next, a 10 s average filter is applied to both signals to decimate it to 0.1 Hz, limiting the influence of faster slow frequencies related to breathing. Next, using moving Pearson linear correlation coefficients, typically based on 30 consecutive (10 s averaged) values updated every minute (i.e. 5 min of data, updated every minute), an index of cerebrovascular reactivity is derived. The classic, and most commonly used, example in adult TBI is the pressure reactivity index (PRx),
      • Czosnyka M.
      • Smielewski P.
      • Kirkpatrick P.
      • Laing R.J.
      • Menon D.
      • Pickard J.D.
      Continuous assessment of the cerebral vasomotor reactivity in head injury.
      which is derived from the moving correlation between slow waves of ICP (surrogate of changes in CBV) and MAP (surrogate of changes in the driving pressure). In general, cerebrovascular reactivity index values that are positive denote ‘impaired’ autoregulation and describe passive transition of driving pressure influence on CBV. Values that are negative or around zero are believed to denote ‘intact’ autoregulation by active filtering the transition of slow waves. Fig. 3 provides a diagrammatic representation of the calculation method for PRx from raw high-frequency physiologic data. Furthermore, these continuously updating methods have led to the ability to derive individual physiologic targets in adult TBI.
      • Steiner L.A.
      • Czosnyka M.
      • Piechnik S.K.
      • et al.
      Continuous monitoring of cerebrovascular pressure reactivity allows determination of optimal cerebral perfusion pressure in patients with traumatic brain injury.
      ,
      • Aries M.J.H.
      • Czosnyka M.
      • Budohoski K.P.
      • et al.
      Continuous determination of optimal cerebral perfusion pressure in traumatic brain injury.
      The next section will discuss in more detail various continuous cerebrovascular reactivity measures currently described in the adult TBI literature.
      Fig 3
      Fig 3Diagrammatic representation of PRx calculation from high-frequency physiology. An example showing how the PRx index (trend) is calculated over a period of several hours. First, from the bedside monitor the raw signals of ABP and ICP are collected in dedicated ICM+© software (Cambridge Enterprise Ltd, Cambridge, UK, http://icmplus.neurosurg.cam.ac.uk). The characteristic waveform of the signals are clearly visible. Both signals are averaged over a 10 s period to retrieve the mean ABP (MAP) and mean ICP (MICP) value. Averaging is necessary to limit the influence of artifacts and ventilation on the autoregulation calculations. Next, over a period of 300 s (5 min) the Pearson correlation between MAP and MICP is calculated. This calculation process is repeated with a moving window of 60 s (so 80% overlap of data is present). Finally, this gives us the time trend of the PRx index. The whole calculations process can be done offline (after data storage) or online (at the bedside). ABP, arterial blood pressure; ICP, intracranial pressure; PRx, pressure reactivity index.

      Currently used continuous monitors of cerebrovascular reactivity in adult traumatic brain injury

       Continuous multimodal monitoring metrics

      Based on the concept of evaluating the relationship between spontaneous slow-wave vasogenic fluctuations in signals, as described above, various measures of cerebrovascular reactivity can be derived using a range of invasive and noninvasive continuous MMM used in the assessment of critically ill TBI patients.
      • Zeiler F.A.
      • Donnelly J.
      • Calviello L.
      • Smielewski P.
      • Menon D.K.
      • Czosnyka M.
      Pressure autoregulation measurement techniques in adult traumatic brain injury: Part II. A scoping review of continuous methods.
      ,
      • Klein S.P.
      • Depreitere B.
      • Meyfroidt G.
      How I monitor cerebral autoregulation.
      ,
      • Calviello L.A.
      • Donnelly J.
      • Zeiler F.A.
      • Thelin E.P.
      • Smielewski P.
      • Czosnyka M.
      Cerebral autoregulation monitoring in acute traumatic brain injury: what’s the evidence?.
      The currently described techniques include those cerebrovascular reactivity indices derived from: ICP, transcranial Doppler (TCD), NIRS, brain tissue oxygen (PbtO2), and thermal diffusion CBF (TD-CBF) monitoring. Appendix C of the online Supplementary material provides an overview of the different cerebral monitoring devices, and the related cerebrovascular reactivity metrics.
      The signal based metrics can be divided into three main classes: (1) those that are based on surrogate measure of changes in CBV,
      • Czosnyka M.
      • Smielewski P.
      • Kirkpatrick P.
      • Laing R.J.
      • Menon D.
      • Pickard J.D.
      Continuous assessment of the cerebral vasomotor reactivity in head injury.
      ,
      • Aries M.J.H.
      • Czosnyka M.
      • Budohoski K.P.
      • et al.
      Continuous monitoring of cerebrovascular reactivity using pulse waveform of intracranial pressure.
      • Zeiler F.A.
      • Donnelly J.
      • Menon D.K.
      • Smielewski P.
      • Hutchinson P.J.A.
      • Czosnyka M.
      A description of a new continuous physiological index in traumatic brain injury using the correlation between pulse amplitude of intracranial pressure and cerebral perfusion pressure.
      • Zweifel C.
      • Castellani G.
      • Czosnyka M.
      • et al.
      Noninvasive monitoring of cerebrovascular reactivity with near infrared spectroscopy in head-injured patients.
      • Diedler J.
      • Zweifel C.
      • Budohoski K.P.
      • et al.
      The limitations of near-infrared spectroscopy to assess cerebrovascular reactivity: the role of slow frequency oscillations.
      • Highton D.
      • Ghosh A.
      • Tachtsidis I.
      • Panovska-Griffiths J.
      • Elwell C.E.
      • Smith M.
      Monitoring cerebral autoregulation after brain injury: multimodal assessment of cerebral slow-wave oscillations using near-infrared spectroscopy.
      • Highton D.
      • Ghosh A.
      • Tachtsidis I.
      • Kolyva C.
      • Elwell C.
      • Smith M.
      A comparison between pressure reactivity index, mean velocity index, and near infrared spectroscopy in brain injury.
      (2) those based on surrogate measures of changes in CBF,
      • Sorrentino E.
      • Budohoski K.P.
      • Kasprowicz M.
      • et al.
      Critical thresholds for transcranial Doppler indices of cerebral autoregulation in traumatic brain injury.
      • Zeiler F.A.
      • Cardim D.
      • Donnelly J.
      • Menon D.K.
      • Czosnyka M.
      • Smielewski P.
      Transcranial Doppler systolic flow index and ICP-derived cerebrovascular reactivity indices in traumatic brain injury.
      • Budohoski K.P.
      • Reinhard M.
      • Aries M.J.H.
      • et al.
      Monitoring cerebral autoregulation after head injury. Which component of transcranial Doppler flow velocity is optimal?.
      • Rosenthal G.
      • Hemphill J.C.
      • Manley G.
      Brain tissue oxygen tension is more indicative of oxygen diffusion than oxygen delivery and metabolism in patients with traumatic brain injury.
      • Rosenthal G.
      • Sanchez-Mejia R.O.
      • Phan N.
      • Hemphill J.C.
      • Martin C.
      • Manley G.T.
      Incorporating a parenchymal thermal diffusion cerebral blood flow probe in bedside assessment of cerebral autoregulation and vasoreactivity in patients with severe traumatic brain injury.
      • Oshorov A.
      • Savin I.
      • Popugaev K.
      • Potopov A.
      Influence of hyperthermia on the parameters of MAP, CPP and PRx in patients with severe TBI.
      • Dias C.
      • Silva M.J.
      • Pereira E.
      • et al.
      Post-traumatic multimodal brain monitoring: response to hypertonic saline.
      and (3) those based on cerebral physiologic metrics other than CBV or CBF.
      • Jaeger M.
      • Lang E.W.
      Cerebrovascular pressure reactivity and cerebral oxygen regulation after severe head injury.
      • Radolovich D.K.
      • Czosnyka M.
      • Timofeev I.
      • et al.
      Reactivity of brain tissue oxygen to change in cerebral perfusion pressure in head injured patients.
      • Dias C.
      • Silva M.J.
      • Pereira E.
      • et al.
      Optimal cerebral perfusion pressure management at bedside: a single-center pilot study.
      • Dias C.
      • Maia I.
      • Cerejo A.
      • et al.
      Pressures, flow, and brain oxygenation during plateau waves of intracranial pressure.
      As highlighted by three recent retrospective cohort studies in adult TBI, these continuous indices are not all equivalent, nor do they all measure the same aspect of the cerebrovascular reactivity process.
      • Zeiler F.A.
      • Cardim D.
      • Donnelly J.
      • Menon D.K.
      • Czosnyka M.
      • Smielewski P.
      Transcranial Doppler systolic flow index and ICP-derived cerebrovascular reactivity indices in traumatic brain injury.
      ,
      • Zeiler F.A.
      • Donnelly J.
      • Menon D.K.
      • et al.
      Continuous autoregulatory indices derived from multimodal monitoring: each one is not like the other.
      ,
      • Zeiler F.A.
      • Donnelly J.
      • Cardim D.
      • Menon D.K.
      • Smielewski P.
      • Czosnyka M.
      ICP versus laser Doppler cerebrovascular reactivity indices to assess brain autoregulatory capacity.
      To date, only a few metrics have been validated as a measure of autoregulation experimentally. Therefore, we will focus on these, with the remaining MMM metrics described in Appendix C of the online Supplementary material.

       Intracranial pressure and near-infrared spectroscopy monitoring

      ICP and NIRS monitoring provide the most commonly applied CBV-based metrics of continuous cerebrovascular reactivity.
      • Czosnyka M.
      • Smielewski P.
      • Kirkpatrick P.
      • Laing R.J.
      • Menon D.
      • Pickard J.D.
      Continuous assessment of the cerebral vasomotor reactivity in head injury.
      ,
      • Aries M.J.H.
      • Czosnyka M.
      • Budohoski K.P.
      • et al.
      Continuous monitoring of cerebrovascular reactivity using pulse waveform of intracranial pressure.
      • Zeiler F.A.
      • Donnelly J.
      • Menon D.K.
      • Smielewski P.
      • Hutchinson P.J.A.
      • Czosnyka M.
      A description of a new continuous physiological index in traumatic brain injury using the correlation between pulse amplitude of intracranial pressure and cerebral perfusion pressure.
      • Zweifel C.
      • Castellani G.
      • Czosnyka M.
      • et al.
      Noninvasive monitoring of cerebrovascular reactivity with near infrared spectroscopy in head-injured patients.
      • Diedler J.
      • Zweifel C.
      • Budohoski K.P.
      • et al.
      The limitations of near-infrared spectroscopy to assess cerebrovascular reactivity: the role of slow frequency oscillations.
      ,
      • Highton D.
      • Ghosh A.
      • Tachtsidis I.
      • Kolyva C.
      • Elwell C.
      • Smith M.
      A comparison between pressure reactivity index, mean velocity index, and near infrared spectroscopy in brain injury.
      ICP-based indices are considered the ‘standard’ by many experts in the field given the robust signals and experimental literature supporting them (see next section).
      • Brady K.M.
      • Lee J.K.
      • Kibler K.K.
      • Easley R.B.
      • Koehler R.C.
      • Shaffner D.H.
      Continuous measurement of autoregulation by spontaneous fluctuations in cerebral perfusion pressure: comparison of 3 methods.
      • Zeiler F.A.
      • Donnelly J.
      • Calviello L.
      • et al.
      Validation of pressure reactivity and pulse amplitude indices against the lower limit of autoregulation: Part I. Experimental intra-cranial hypertension.
      • Zeiler F.A.
      • Lee J.K.
      • Smielewski P.
      • Czosnyka M.
      • Brady K.
      Validation of ICP derived cerebrovascular reactivity indices against the lower limit of autoregulation: Part II. Experimental model of arterial hypotension.
      They provide global information regarding cerebrovascular reactivity using the ICP
      • Czosnyka M.
      • Smielewski P.
      • Kirkpatrick P.
      • Laing R.J.
      • Menon D.
      • Pickard J.D.
      Continuous assessment of the cerebral vasomotor reactivity in head injury.
      or the pulse amplitude of ICP (AMP)
      • Aries M.J.H.
      • Czosnyka M.
      • Budohoski K.P.
      • et al.
      Continuous monitoring of cerebrovascular reactivity using pulse waveform of intracranial pressure.
      ,
      • Zeiler F.A.
      • Donnelly J.
      • Menon D.K.
      • Smielewski P.
      • Hutchinson P.J.A.
      • Czosnyka M.
      A description of a new continuous physiological index in traumatic brain injury using the correlation between pulse amplitude of intracranial pressure and cerebral perfusion pressure.
      as a surrogate of slow changes in CBV. Lower resolution metrics for ICP-derived cerebrovascular reactivity indices exist, but are not commonly used clinically, and are beyond the scope of this review. Appendix D of the online Supplementary material provides a brief description of these low-resolution metrics and the relevant associated literature.
      Bifrontal NIRS measurement information regarding changes in oxygenated and deoxygenated haemoglobin that are caused by changes in CBV is used to calculate cerebrovascular reactivity. The theory behind this is that an increase in intracranial volume is compensated by arterial or venous components. In comatose patient with low metabolic activity, we therefore expect the total Hb, as the sum of oxygenated and deoxygenated Hb, to remain constant. In case of multi-channel NIRS application, regional vasoregulation or homeostatic information is obtained.
      • Zweifel C.
      • Castellani G.
      • Czosnyka M.
      • et al.
      Noninvasive monitoring of cerebrovascular reactivity with near infrared spectroscopy in head-injured patients.
      • Diedler J.
      • Zweifel C.
      • Budohoski K.P.
      • et al.
      The limitations of near-infrared spectroscopy to assess cerebrovascular reactivity: the role of slow frequency oscillations.
      • Highton D.
      • Ghosh A.
      • Tachtsidis I.
      • Panovska-Griffiths J.
      • Elwell C.E.
      • Smith M.
      Monitoring cerebral autoregulation after brain injury: multimodal assessment of cerebral slow-wave oscillations using near-infrared spectroscopy.
      • Highton D.
      • Ghosh A.
      • Tachtsidis I.
      • Kolyva C.
      • Elwell C.
      • Smith M.
      A comparison between pressure reactivity index, mean velocity index, and near infrared spectroscopy in brain injury.
      ,
      • Highton D.
      • Ghosh A.
      • Tachtsidis I.
      • et al.
      Deoxyhaemoglobin as a biomarker of cerebral autoregulation.
      NIRS also may provide some information regarding the contribution of changes in CBF, but differentiation from accompanying CBV changes at the same time is difficult.
      • Highton D.
      • Ghosh A.
      • Tachtsidis I.
      • Panovska-Griffiths J.
      • Elwell C.E.
      • Smith M.
      Monitoring cerebral autoregulation after brain injury: multimodal assessment of cerebral slow-wave oscillations using near-infrared spectroscopy.
      ,
      • Highton D.
      • Ghosh A.
      • Tachtsidis I.
      • Kolyva C.
      • Elwell C.
      • Smith M.
      A comparison between pressure reactivity index, mean velocity index, and near infrared spectroscopy in brain injury.
      ,
      • Highton D.
      • Ghosh A.
      • Tachtsidis I.
      • et al.
      Deoxyhaemoglobin as a biomarker of cerebral autoregulation.
      ,
      • Mathieu F.
      • Khellaf A.
      • Ku J.
      • Donnelly J.
      • Thelin E.P.
      • Zeiler F.A.
      Continuous near-infrared spectroscopy monitoring in adult traumatic brain injury: a scoping systematic review.
      Both ICP and NIRS indices have, to some extent, been validated in experimental animal models (see next section).
      • Brady K.M.
      • Lee J.K.
      • Kibler K.K.
      • Easley R.B.
      • Koehler R.C.
      • Shaffner D.H.
      Continuous measurement of autoregulation by spontaneous fluctuations in cerebral perfusion pressure: comparison of 3 methods.
      • Zeiler F.A.
      • Donnelly J.
      • Calviello L.
      • et al.
      Validation of pressure reactivity and pulse amplitude indices against the lower limit of autoregulation: Part I. Experimental intra-cranial hypertension.
      • Zeiler F.A.
      • Lee J.K.
      • Smielewski P.
      • Czosnyka M.
      • Brady K.
      Validation of ICP derived cerebrovascular reactivity indices against the lower limit of autoregulation: Part II. Experimental model of arterial hypotension.
      ,
      • Joshi B.
      • Brady K.
      • Lee J.
      • et al.
      Impaired autoregulation of cerebral blood flow during rewarming from hypothermic cardiopulmonary bypass and its potential association with stroke.

       Experimental validation studies

      Of all the described continuous cerebrovascular reactivity measures in adult TBI, very few have received pre-clinical experimental validation as true measures of autoregulation in animal models. To date, only ICP-based PRx,
      • Brady K.M.
      • Lee J.K.
      • Kibler K.K.
      • Easley R.B.
      • Koehler R.C.
      • Shaffner D.H.
      Continuous measurement of autoregulation by spontaneous fluctuations in cerebral perfusion pressure: comparison of 3 methods.
      • Zeiler F.A.
      • Donnelly J.
      • Calviello L.
      • et al.
      Validation of pressure reactivity and pulse amplitude indices against the lower limit of autoregulation: Part I. Experimental intra-cranial hypertension.
      • Zeiler F.A.
      • Lee J.K.
      • Smielewski P.
      • Czosnyka M.
      • Brady K.
      Validation of ICP derived cerebrovascular reactivity indices against the lower limit of autoregulation: Part II. Experimental model of arterial hypotension.
      PAx (correlation between AMP and MAP),
      • Zeiler F.A.
      • Donnelly J.
      • Calviello L.
      • et al.
      Validation of pressure reactivity and pulse amplitude indices against the lower limit of autoregulation: Part I. Experimental intra-cranial hypertension.
      ,
      • Zeiler F.A.
      • Lee J.K.
      • Smielewski P.
      • Czosnyka M.
      • Brady K.
      Validation of ICP derived cerebrovascular reactivity indices against the lower limit of autoregulation: Part II. Experimental model of arterial hypotension.
      and RAC
      • Zeiler F.A.
      • Lee J.K.
      • Smielewski P.
      • Czosnyka M.
      • Brady K.
      Validation of ICP derived cerebrovascular reactivity indices against the lower limit of autoregulation: Part II. Experimental model of arterial hypotension.
      (correlation [R] between AMP [A] and CPP [C]) have data to support that they can detect the lower limit of autoregulation (LLA) during arterial hypotension and intracranial hypertension. NIRS based THx (or HVx; correlation between total haemoglobin index [THI] and CPP) and total oxygenation index (TOx or COx; correlation between total oxygen index [TOI] or regional oxygen saturation [rSO2] and CPP) have only been assessed in experimental arterial hypotension, confirming that these measures provide information regarding the LLA.
      • Brady K.M.
      • Lee J.K.
      • Kibler K.K.
      • Easley R.B.
      • Koehler R.C.
      • Shaffner D.H.
      Continuous measurement of autoregulation by spontaneous fluctuations in cerebral perfusion pressure: comparison of 3 methods.
      ,
      • Joshi B.
      • Brady K.
      • Lee J.
      • et al.
      Impaired autoregulation of cerebral blood flow during rewarming from hypothermic cardiopulmonary bypass and its potential association with stroke.
      All other intracranial based metrics have either never been evaluated experimentally against the LLA or upper limit of autoregulation (ULA), or have displayed inconclusive results. Of note, there are currently no data which document that these continuous metrics of cerebrovascular reactivity reliably measure the ULA, as such validation is subject to model limitations (i.e. animals succumbing to cardiac failure prior to MAP reaching and surpassing the ULA).
      • Pesek M.
      • Kibler K.
      • Easley R.B.
      • et al.
      The upper limit of cerebral blood flow autoregulation is decreased with elevations in intracranial pressure.
      ,
      • Pesek M.
      • Kibler K.
      • Easley R.B.
      • et al.
      The upper limit of cerebral blood flow autoregulation is decreased with elevations in intracranial pressure.
      This aspect requires further exploration.

      Physiologic and outcome associations with continuously measured cerebrovascular reactivity in traumatic brain injury

      Given the myriad of cerebrovascular reactivity metrics available, the literature on this topic in adult TBI can be daunting. In the following section, we summarise the important literature regarding associations between continuously measured cerebrovascular reactivity and both cerebral physiologic measures and patient outcome. For simplicity, we will focus on the MAP (input) and CBV/ICP (output)-derived measures (mainly PRx), given the extensive literature on these measures,
      • Zeiler F.A.
      • Donnelly J.
      • Calviello L.
      • Smielewski P.
      • Menon D.K.
      • Czosnyka M.
      Pressure autoregulation measurement techniques in adult traumatic brain injury: Part II. A scoping review of continuous methods.
      their acceptance by the international community,
      • Le Roux P.
      • Menon D.K.
      • Citerio G.
      • et al.
      The International Multidisciplinary Consensus Conference on Multimodality Monitoring in Neurocritical Care: evidentiary tables: a statement for healthcare professionals from the neurocritical care society and the European society of intensive care medicine.
      ,
      • Czosnyka M.
      • Miller C.
      Participants in the international multidisciplinary consensus conference on multimodality monitoring. Monitoring of cerebral autoregulation.
      and existence of experimental data supporting them as measures of the LLA.
      • Brady K.M.
      • Lee J.K.
      • Kibler K.K.
      • Easley R.B.
      • Koehler R.C.
      • Shaffner D.H.
      Continuous measurement of autoregulation by spontaneous fluctuations in cerebral perfusion pressure: comparison of 3 methods.
      • Zeiler F.A.
      • Donnelly J.
      • Calviello L.
      • et al.
      Validation of pressure reactivity and pulse amplitude indices against the lower limit of autoregulation: Part I. Experimental intra-cranial hypertension.
      • Zeiler F.A.
      • Lee J.K.
      • Smielewski P.
      • Czosnyka M.
      • Brady K.
      Validation of ICP derived cerebrovascular reactivity indices against the lower limit of autoregulation: Part II. Experimental model of arterial hypotension.

       Association with patient and injury factors

      Continuously measured PRx has been evaluated in various studies in adult TBI. Specific recurring associations between patient demographics have been identified. First, advanced age appears to be associated with worse autoregulatory function in moderate/severe TBI, with those above the age of 60 yr demonstrating the worst measures.
      • Czosnyka M.
      • Balestreri M.
      • Steiner L.
      • et al.
      Age, intracranial pressure, autoregulation, and outcome after brain trauma.
      ,
      • Zeiler F.A.
      • Donnelly J.
      • Smielewski P.
      • Menon D.K.
      • Hutchinson P.J.
      • Czosnyka M.
      Critical thresholds of intracranial pressure-derived continuous cerebrovascular reactivity indices for outcome prediction in noncraniectomized patients with traumatic brain injury.
      Second, although the data are limited, there is some suggestion that females younger than 50 yr display worse cerebrovascular reactivity after moderate/severe TBI compared with their male counterparts (males, PRx 0.044 [sd 0.031]; females, PRx 0.11 [0.047]; P<0.05),
      • Balestreri M.
      • Steiner L.A.
      • Czosnyka M.
      Sex-related differences and traumatic brain injury.
      although this finding requires validation with control for co-variates. Third, low admission Glasgow Coma Scale (GCS) score was associated with poor cerebrovascular reactivity during the ICU monitoring period (r=0.29; P<0.01).
      • Czosnyka M.
      • Smielewski P.
      • Kirkpatrick P.
      • Laing R.J.
      • Menon D.
      • Pickard J.D.
      Continuous assessment of the cerebral vasomotor reactivity in head injury.
      Fourth, admission intracranial injury burden, as assessed using CT, has been demonstrated to be associated with worse cerebrovascular reactivity during the acute ICU stay.
      • Hiler M.
      • Czosnyka M.
      • Hutchinson P.
      • et al.
      Predictive value of initial computerized tomography scan, intracranial pressure, and state of autoregulation in patients with traumatic brain injury.
      ,
      • Zeiler F.A.
      • Donnelly J.
      • Nourallah B.
      • et al.
      Intracranial and extracranial injury burden as drivers of impaired cerebrovascular reactivity in traumatic brain injury.
      In particular, specific injury patterns associated with acceleration/deceleration or shearing mechanisms display the strongest link to globally impaired vascular reactivity.
      • Zeiler F.A.
      • Donnelly J.
      • Nourallah B.
      • et al.
      Intracranial and extracranial injury burden as drivers of impaired cerebrovascular reactivity in traumatic brain injury.
      Such injury characteristics include presence of a subdural haematoma, traumatic subarachnoid haemorrhage, and sub-cortical diffuse axonal injury. These findings suggest that these particular high energy injury mechanisms appear to predispose adult TBI patients to develop sustained impaired cerebrovascular reactivity during their ICU stay. Finally, admission Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) scores, but not injury severity scores, are strongly associated with impaired cerebrovascular reactivity metrics.
      • Zeiler F.A.
      • Donnelly J.
      • Nourallah B.
      • et al.
      Intracranial and extracranial injury burden as drivers of impaired cerebrovascular reactivity in traumatic brain injury.
      This suggests that the extracranial injury burden is not necessarily an additional driver of impaired vascular reactivity, but the individual systemic stress response to trauma may drive impaired cerebrovascular reactivity. These findings raise questions as to the role of the autonomic nervous system,
      • Lavinio A.
      • Ene-Iordache B.
      • Nodari I.
      • et al.
      Cerebrovascular reactivity and autonomic drive following traumatic brain injury.
      ,
      • Sykora M.
      • Czosnyka M.
      • Liu X.
      • et al.
      Autonomic impairment in severe traumatic brain injury: a multimodal neuromonitoring study.
      ,
      • Hasen M.A.
      • Almojuela A.
      • Zeiler F.A.
      Autonomic dysfunction and associations with functional and neurophysiologic outcome in moderate/severe traumatic brain injury: a scoping review.
      inflammatory mediators,
      • Thelin E.P.
      • Tajsic T.
      • Zeiler F.A.
      • et al.
      Monitoring the neuroinflammatory response following acute brain injury.
      ,
      • Helmy A.
      • De Simoni M.-G.
      • Guilfoyle M.R.
      • Carpenter K.L.H.
      • Hutchinson P.J.
      Cytokines and innate inflammation in the pathogenesis of human traumatic brain injury.
      ,
      • Zeiler F.A.
      • Thelin E.P.
      • Czosnyka M.
      • Hutchinson P.J.
      • Menon D.K.
      • Helmy A.
      Cerebrospinal fluid and microdialysis cytokines in severe traumatic brain injury: a scoping systematic review.
      and TBI therapeutic interventions (e.g. deep sedation, fluids, cooling, transfusion)
      • Donnelly J.
      • Czosnyka M.
      • Adams H.
      • et al.
      Twenty-five years of intracranial pressure monitoring after severe traumatic brain injury: a retrospective, single-center analysis.
      ,
      • Weersink C.S.A.
      • Aries M.J.H.
      • Dias C.
      • et al.
      Clinical and physiological events that contribute to the success rate of finding ‘optimal’ cerebral perfusion pressure in severe brain trauma patients.
      ,
      • Zeiler F.A.
      • Ercole A.
      • Beqiri E.
      • et al.
      Cerebrovascular reactivity is not associated with therapeutic intensity in adult traumatic brain injury: a CENTER-TBI analysis.
      ,
      • Sekhon M.S.
      • Griesdale D.E.
      • Czosnyka M.
      • et al.
      The effect of red blood cell transfusion on cerebral autoregulation in patients with severe traumatic brain injury.
      in the acute phase, in driving impaired autoregulation in TBI. Further investigation of all of the above patient and injury factors is ongoing as part of the CENTER-TBI High Resolution ICU Sub-Study objectives.

       Association with continuously monitored cerebral physiology

      There have been a large number of studies assessing the correlation and association between cerebrovascular reactivity monitoring and other continuously measured cerebral physiology in adult moderate/severe TBI.
      • Zeiler F.A.
      • Donnelly J.
      • Calviello L.
      • Smielewski P.
      • Menon D.K.
      • Czosnyka M.
      Pressure autoregulation measurement techniques in adult traumatic brain injury: Part II. A scoping review of continuous methods.
      Elevated ICP has been well documented to be associated with worse cerebrovascular reactivity,
      • Güiza F.
      • Depreitere B.
      • Piper I.
      • et al.
      Visualizing the pressure and time burden of intracranial hypertension in adult and paediatric traumatic brain injury.
      ,
      • Güiza F.
      • Meyfroidt G.
      • Piper I.
      • et al.
      Cerebral perfusion pressure insults and associations with outcome in adult traumatic brain injury.
      ,
      • Adams H.
      • Donelly J.
      • Kolias A.
      • et al.
      Characterising the temporal evolution of ICP and cerebrovascular reactivity after severe traumatic brain injury: best international abstract award.
      and appears to be a key physiologic driver of ongoing impairment. CPP values at both upper and lower extremes are associated with worse cerebrovascular reactivity,
      • Donnelly J.
      • Czosnyka M.
      • Adams H.
      • et al.
      Individualizing thresholds of cerebral perfusion pressure using estimated limits of autoregulation.
      and form the basis for individualised CPP targets or target range in adult TBI care, summarised as the ‘optimal’ CPP concept. This refers to the concept of a ‘safe’ autoregulation plateau (see following sections for further discussion).
      • Steiner L.A.
      • Czosnyka M.
      • Piechnik S.K.
      • et al.
      Continuous monitoring of cerebrovascular pressure reactivity allows determination of optimal cerebral perfusion pressure in patients with traumatic brain injury.
      ,
      • Aries M.J.H.
      • Czosnyka M.
      • Budohoski K.P.
      • et al.
      Continuous determination of optimal cerebral perfusion pressure in traumatic brain injury.
      ,
      • Donnelly J.
      • Czosnyka M.
      • Adams H.
      • et al.
      Individualizing thresholds of cerebral perfusion pressure using estimated limits of autoregulation.
      ,
      • Needham E.
      • McFadyen C.
      • Newcombe V.
      • Synnot A.J.
      • Czosnyka M.
      • Menon D.
      Cerebral perfusion pressure targets individualized to pressure-reactivity index in moderate to severe traumatic brain injury: a systematic review.
      The specific CPP thresholds associated with impaired vascular reactivity are individual and dynamic, and are related to combinations of physiologic factors, such as ICP, chronic systemic hypertension, and degree of baseline cardiovascular and pulmonary fitness.
      • Winn H.
      Youmans neurological surgery.
      • Armstead W.M.
      Cerebral blood flow autoregulation and dysautoregulation.
      • Ungvari Z.
      • Tarantini S.
      • Kirkpatrick A.C.
      • Csiszar A.
      • Prodan C.I.
      Cerebral microhemorrhages: mechanisms, consequences, and prevention.
      • Kisler K.
      • Nelson A.R.
      • Montagne A.
      • Zlokovic B.V.
      Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease.
      As such, these individualised CPP thresholds can be seen as a ‘moving’ value, dependent on patient baseline factors, and ongoing factors related to the injury and treatment.
      In keeping with the relationship between CPP and PRx—although the number of clinical studies with invasive continuously measured CBF are limited—there does exist some preliminary data, using LDF or TD-CBF, to support the temporal relationship between reduced local CBF and impaired PRx measures.
      • Dias C.
      • Silva M.J.
      • Pereira E.
      • et al.
      Post-traumatic multimodal brain monitoring: response to hypertonic saline.
      ,
      • Dias C.
      • Silva M.J.
      • Pereira E.
      • et al.
      Optimal cerebral perfusion pressure management at bedside: a single-center pilot study.
      ,
      • Dias C.
      • Maia I.
      • Cerejo A.
      • Smielewski P.
      • Paiva J.-A.
      • Czosnyka M.
      Plateau waves of intracranial pressure and multimodal brain monitoring.
      The relationship between other MMM physiologic variables and PRx in adult TBI are less commonly described. A brief overview of these findings and the relevant literature can be found in Appendix E of the online Supplementary material.

       Association with outcome

      Numerous studies confirm the association between continuously measured PRx and global outcome.
      • Sorrentino E.
      • Diedler J.
      • Kasprowicz M.
      • et al.
      Critical thresholds for cerebrovascular reactivity after traumatic brain injury.
      ,
      • Zeiler F.A.
      • Ercole A.
      • Cabeleira M.
      • et al.
      Univariate comparison of performance of different cerebrovascular reactivity indices for outcome association in adult TBI: a CENTER-TBI study.
      ,
      • Czosnyka M.
      • Smielewski P.
      • Kirkpatrick P.
      • Laing R.J.
      • Menon D.
      • Pickard J.D.
      Continuous assessment of the cerebral vasomotor reactivity in head injury.
      ,
      • Zeiler F.A.
      • Donnelly J.
      • Calviello L.
      • Smielewski P.
      • Menon D.K.
      • Czosnyka M.
      Pressure autoregulation measurement techniques in adult traumatic brain injury: Part II. A scoping review of continuous methods.
      ,
      • Zeiler F.A.
      • Donnelly J.
      • Smielewski P.
      • Menon D.K.
      • Hutchinson P.J.
      • Czosnyka M.
      Critical thresholds of intracranial pressure-derived continuous cerebrovascular reactivity indices for outcome prediction in noncraniectomized patients with traumatic brain injury.
      Czosnyka and colleagues
      • Czosnyka M.
      • Smielewski P.
      • Kirkpatrick P.
      • Laing R.J.
      • Menon D.
      • Pickard J.D.
      Continuous assessment of the cerebral vasomotor reactivity in head injury.
      documented the first associations between continuously measured cerebrovascular reactivity in moderate/severe adult TBI and global outcome in 1997 (r=0.48; P<0.00001). This study has sparked various other retrospective assessments of cerebrovascular reactivity summarised over the whole monitoring period and its association with global patient outcome. One such (single-centre) study, evaluating 25 yr of neuro-monitoring in 1146 critically ill adult TBI patients, displayed the persistently strong association between outcome and PRx despite changes in BTF based guidelines over time.
      • Donnelly J.
      • Czosnyka M.
      • Adams H.
      • et al.
      Twenty-five years of intracranial pressure monitoring after severe traumatic brain injury: a retrospective, single-center analysis.
      Moreover, PRx has distinct critical thresholds associated with poor global outcome at 6 months, including thresholds of 0, +0.25, and +0.35.
      • Sorrentino E.
      • Diedler J.
      • Kasprowicz M.
      • et al.
      Critical thresholds for cerebrovascular reactivity after traumatic brain injury.
      ,
      • Zeiler F.A.
      • Donnelly J.
      • Smielewski P.
      • Menon D.K.
      • Hutchinson P.J.
      • Czosnyka M.
      Critical thresholds of intracranial pressure-derived continuous cerebrovascular reactivity indices for outcome prediction in noncraniectomized patients with traumatic brain injury.
      The other ICP-derived cerebrovascular reactivity indices, PAx and RAC, also display critical thresholds associated with outcome.
      • Zeiler F.A.
      • Donnelly J.
      • Smielewski P.
      • Menon D.K.
      • Hutchinson P.J.
      • Czosnyka M.
      Critical thresholds of intracranial pressure-derived continuous cerebrovascular reactivity indices for outcome prediction in noncraniectomized patients with traumatic brain injury.
      In addition, a recent retrospective analysis, controlling for admission demographics and other physiologic variables, has confirmed the persistently strong association between impaired cerebrovascular reactivity (measured as PRx, PAx, or RAC), with 6 month outcome.
      • Zeiler F.A.
      • Donnelly J.
      • Smielewski P.
      • Menon D.K.
      • Hutchinson P.J.
      • Czosnyka M.
      Critical thresholds of intracranial pressure-derived continuous cerebrovascular reactivity indices for outcome prediction in noncraniectomized patients with traumatic brain injury.
      This study also displayed higher area under the receiver operating curve (AUC) for prognostic models including cerebrovascular reactivity indices, compared with baseline models with patient demographics, ICP, and CPP physiologic measures. These results suggest added prognostic value of vascular reactivity monitoring in adult TBI above standard ICP/CPP monitoring and call for new interventions. Furthermore, recent publications from the prospective multi-centre CENTER-TBI High Resolution ICU Sub-Study have confirmed the above-mentioned associations with outcome,
      • Zeiler F.A.
      • Ercole A.
      • Cabeleira M.
      • et al.
      Univariate comparison of performance of different cerebrovascular reactivity indices for outcome association in adult TBI: a CENTER-TBI study.
      ,
      • Zeiler F.A.
      • Ercole A.
      • Cabeleira M.
      • et al.
      Comparison of performance of different optimal cerebral perfusion pressure parameters for outcome prediction in adult TBI: a CENTER-TBI study.
      providing additional confidence in the results from previous retrospective studies.

      Current status of treatment for dysfunctional cerebrovascular reactivity in traumatic brain injury

      Despite the strong links between impaired cerebrovascular reactivity and patient outcome, current BTF based therapies pay limited attention to continuous updated vascular reactivity status.
      • Donnelly J.
      • Czosnyka M.
      • Adams H.
      • et al.
      Twenty-five years of intracranial pressure monitoring after severe traumatic brain injury: a retrospective, single-center analysis.
      ,
      • Weersink C.S.A.
      • Aries M.J.H.
      • Dias C.
      • et al.
      Clinical and physiological events that contribute to the success rate of finding ‘optimal’ cerebral perfusion pressure in severe brain trauma patients.
      ,
      • Zeiler F.A.
      • Ercole A.
      • Beqiri E.
      • et al.
      Cerebrovascular reactivity is not associated with therapeutic intensity in adult traumatic brain injury: a CENTER-TBI analysis.
      A large 25 yr retrospective single-centre study, analysing 1146 critically ill TBI patients with invasive ICP monitoring, provides some evidence to support the lack of BTF-based treatment effect on continuously measures cerebrovascular reactivity.
      • Donnelly J.
      • Czosnyka M.
      • Adams H.
      • et al.
      Twenty-five years of intracranial pressure monitoring after severe traumatic brain injury: a retrospective, single-center analysis.
      Within this analysis, ICP, CPP and PRx were assessed in each patient across the archived ICU physiology recording period. Patients were split into 5 yr epochs, considering specific BTF guideline changes over these periods. The results clearly showed that ICP and CPP values were controlled in response to changing BTF based guidelines. However, PRx failed to demonstrate any substantial improvement across all assessed epochs. Given this context, it is interesting that the mortality rate for this cohort also remained relatively stable across the 25 yr. As a corollary, the prospective multi-centre CENTER-TBI High Resolution ICU Sub-Study has recently confirmed the relative independence of PRx to treatment measures in the ICU, as measured through daily therapeutic intensity level (TIL) total and sub-scores.
      • Zeiler F.A.
      • Ercole A.
      • Beqiri E.
      • et al.
      Cerebrovascular reactivity is not associated with therapeutic intensity in adult traumatic brain injury: a CENTER-TBI analysis.
      This study also displayed the relative constant time spent with PRx above the value of 0 on a daily basis (as a measure of cerebrovascular reactivity impairment), at 40–50% per day during the first 7 days of ICU care, despite ongoing active care.
      All these results are relevant in the face of the current lack of effective treatment for impaired cerebrovascular reactivity in adult TBI. As such, there is a need for future investigation into potential molecular targets aimed at prevention and treatment of impaired autoregulation. As we wait for such work to be conducted, we are currently left with the difficult situation of patient management in the absence of directed therapies. Consequently, current interest has moved towards individual personalised CPP targets in critically ill TBI patients,
      • Steiner L.A.
      • Czosnyka M.
      • Piechnik S.K.
      • et al.
      Continuous monitoring of cerebrovascular pressure reactivity allows determination of optimal cerebral perfusion pressure in patients with traumatic brain injury.
      ,
      • Aries M.J.H.
      • Czosnyka M.
      • Budohoski K.P.
      • et al.
      Continuous determination of optimal cerebral perfusion pressure in traumatic brain injury.
      ,
      • Needham E.
      • McFadyen C.
      • Newcombe V.
      • Synnot A.J.
      • Czosnyka M.
      • Menon D.
      Cerebral perfusion pressure targets individualized to pressure-reactivity index in moderate to severe traumatic brain injury: a systematic review.
      focussing on achieving CPP values associated with the ‘least–worst’ cerebrovascular reactivity status for a given patient. This concept forms the basis for ‘optimal CPP’ (CPPopt), which will be covered in detail within the next section.

      State-of-the-art personalised cerebral perfusion pressure targets guided by cerebrovascular reactivity monitoring

      The CPPopt concept has gained interest in the past decade with the observation that PRx and CPP often exhibit a U-shaped relationship over time with a minimum PRx occurring at a CPP for which cerebrovascular pressure reactivity is best preserved (or least impaired).
      • Steiner L.A.
      • Czosnyka M.
      • Piechnik S.K.
      • et al.
      Continuous monitoring of cerebrovascular pressure reactivity allows determination of optimal cerebral perfusion pressure in patients with traumatic brain injury.
      Fig. 4 highlights the parabolic relationship seen between PRx and CPP in adult TBI. Such observations suggest that targeting a CPP such that global CA is best maintained is a potentially attractive strategy for individualising TBI care. Deviations in achieved CPP from the CPPopt value (retrospectively assessed) have been associated with worse outcomes.
      • Steiner L.A.
      • Czosnyka M.
      • Piechnik S.K.
      • et al.
      Continuous monitoring of cerebrovascular pressure reactivity allows determination of optimal cerebral perfusion pressure in patients with traumatic brain injury.
      ,
      • Zeiler F.A.
      • Ercole A.
      • Cabeleira M.
      • et al.
      Comparison of performance of different optimal cerebral perfusion pressure parameters for outcome prediction in adult TBI: a CENTER-TBI study.
      ,
      • Aries M.J.H.
      • Czosnyka M.
      • Budohoski K.P.
      • et al.
      Continuous determination of optimal cerebral perfusion pressure in traumatic brain injury.
      ,
      • Svedung Wettervik T.
      • Howells T.
      • Enblad P.
      • Lewén A.
      Temporal neurophysiological dynamics in traumatic brain injury: role of pressure reactivity and optimal cerebral perfusion pressure for predicting outcome.
      ,
      • Donnelly J.
      • Czosnyka M.
      • Adams H.
      • et al.
      Individualizing thresholds of cerebral perfusion pressure using estimated limits of autoregulation.
      ,
      • Needham E.
      • McFadyen C.
      • Newcombe V.
      • Synnot A.J.
      • Czosnyka M.
      • Menon D.
      Cerebral perfusion pressure targets individualized to pressure-reactivity index in moderate to severe traumatic brain injury: a systematic review.
      ,
      • Donnelly J.
      • Czosnyka M.
      • Adams H.
      • et al.
      Pressure reactivity-based optimal cerebral perfusion pressure in a traumatic brain injury cohort.
      ,
      • Kramer A.H.
      • Couillard P.L.
      • Zygun D.A.
      • Aries M.J.
      • Gallagher C.N.
      Continuous assessment of ‘optimal’ cerebral perfusion pressure in traumatic brain injury: a cohort study of feasibility, reliability, and relation to outcome.
      In recent years there has been a great deal of work in trying to translate the concept of autoregulation guided CPP management into an automated clinical application at the bedside. It has been necessary to refine the original algorithms of CPPopt calculation and interface software significantly to allow a continuous assessment that is robust enough for clinical use.
      • Aries M.J.H.
      • Czosnyka M.
      • Budohoski K.P.
      • et al.
      Continuous determination of optimal cerebral perfusion pressure in traumatic brain injury.
      ,
      • Steijn R.
      • Stewart R.
      • Czosnyka M.
      • et al.
      Survey in expert clinicians on the validity of automated calculation of optimal cerebral perfusion pressure.
      ,
      • Liu X.
      • Maurits N.M.
      • Aries M.J.H.
      • et al.
      Monitoring of optimal cerebral perfusion pressure in traumatic brain injured patients using a multi-window weighting algorithm.
      However, to date, prospective evaluation has been lacking. Three prospective pilot studies evaluating CPPopt tailored therapy in different settings demonstrated an improvement in patient physiology and outcome.
      • Dias C.
      • Silva M.J.
      • Pereira E.
      • et al.
      Optimal cerebral perfusion pressure management at bedside: a single-center pilot study.
      ,
      • Jaeger M.
      • Dengl M.
      • Meixensberger J.
      • Schuhmann M.U.
      Effects of cerebrovascular pressure reactivity-guided optimization of cerebral perfusion pressure on brain tissue oxygenation after traumatic brain injury.
      ,
      • Park S.
      • Czosnyka M.
      • Smielewski P.
      Brain oxygen relationship to cerebral perfusion pressure depends on tip location and time window: can brain O2 be an adjunctive modality for determining optimal CPP?.
      However, none of these was a randomised study with a published intervention protocol. It is worthy to note that in the recent Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase II (BOOST II) trial,
      • Okonkwo D.O.
      • Shutter L.A.
      • Moore C.
      • et al.
      Brain oxygen optimization in severe traumatic brain injury phase-II: a phase II randomized trial.
      CPP augmentation higher than 70 mm Hg was a frequent treatment option for increased ICP in the intervention arm (treatment protocol based on combined PbO2 and ICP monitoring). Likely, this resulted in higher levels of CPP in this group or less periods with low CPP, maybe explaining (partly) the improved outcome in the intervention arm.
      • Okonkwo D.O.
      • Shutter L.A.
      • Moore C.
      • et al.
      Brain oxygen optimization in severe traumatic brain injury phase-II: a phase II randomized trial.
      ,
      • Aries M.J.H.
      • Donnelly J.
      Brain Oxygenation optimization after severe traumatic brain injury: an ode to preventing brain hypoxia.
      A prospective study evaluating the feasibility, safety, and the physiological implications of CPPopt guided management is now underway to inform the design of any future phase III study in severe TBI patients (CPPOpt Guided Therapy: Assessment of Target Effectiveness [COGiTATE]; clinicaltrials.gov identifier NCT02982122). Appendix F in the online Supplementary material displays an example CPPopt determination during COGiTATE and the data review steps and intervention.
      Fig 4
      Fig 4Example of CPPopt determination in traumatic brain injury (TBI). This recording in a patient with severe TBI is a snapshot of 4 h period from a recording of several days with invasive ABP and ICP monitoring. Illustration of time series of ABP (a) and ICP (b). (c) Mean PRx values are plotted in 5 mm Hg bins of CPP in this 4 h period; this yields a parabolic or U-shaped curve. The minimum of the PRx indicates the point of best-preserved autoregulation—CPP ‘optimal’ (CPPopt=86 mm Hg)—and is the nadir of the fitted curve. Constructing such 4 h parabolic curves and automated CPPopt values forms the basis of the CPPopt methodology (as described by Aries and colleagues
      • Aries M.J.H.
      • Czosnyka M.
      • Budohoski K.P.
      • et al.
      Continuous determination of optimal cerebral perfusion pressure in traumatic brain injury.
      ). (d) The trends of patients' CPP value (straight line) and CPPopt (dashed line) and also the deviation from CPPopt. To increase the yield and stability of the CPPopt trend a weighted multi-(calculation) window approach was developed and currently under investigation in the COGITATE study (as described by Beqiri and colleagues
      • Beqiri E.
      • Smielewski P.
      • Robba C.
      • et al.
      Feasibility of individualised severe traumatic brain injury management using an automated assessment of optimal cerebral perfusion pressure: the COGiTATE phase II study protocol.
      ). The histogram of time spent in certain CPP values (%) in the lowest panel (e) shows the maximum at lower CPP values, indicating that this patient was predominantly managed at a CPP lower than the ‘optimal’ level. ABP, arterial blood pressure; CPP, cerebral perfusion pressure; CPPopt, optimal CPP; ICP, intracranial pressures; PRx, pressure reactivity index (correlation between slow waves of ICP and ABP).

      Future of cerebrovascular reactivity monitoring in traumatic brain injury

      Existing studies have focused on identifying one autoregulation-guided CPP target, ignoring the fact that a broader CPP range might provide similar autoregulation benefit. As depicted in Fig. 5, understanding the position and shape of CPP-PRx may help us identify the CPP below which PRx is impaired (the lower limit of reactivity [LLR]), the CPP above which PRx is again impaired (upper limit of reactivity [ULR]), and the CPP range associated with intact PRx (within limits of reactivity [WLR]).
      • Needham E.
      • McFadyen C.
      • Newcombe V.
      • Synnot A.J.
      • Czosnyka M.
      • Menon D.
      Cerebral perfusion pressure targets individualized to pressure-reactivity index in moderate to severe traumatic brain injury: a systematic review.
      The time spent with CPP less than LLR and (10 mm Hg) deviation below CPPopt are significantly independently related to adverse outcome, fitting with the clinical maxim that periods with low CPP should be avoided in severe TBI patients.
      • Needham E.
      • McFadyen C.
      • Newcombe V.
      • Synnot A.J.
      • Czosnyka M.
      • Menon D.
      Cerebral perfusion pressure targets individualized to pressure-reactivity index in moderate to severe traumatic brain injury: a systematic review.
      Similar to the recently developed visualisation method of the CPP-PRx landscape,
      • Aries M.J.H.
      • Wesselink R.
      • JWJ Elting
      • et al.
      Enhanced visualization of optimal cerebral perfusion pressure over time to support clinical decision making.
      the continuous estimation of CPP reactivity limits provides the clinician with more contextual information to the single CPPopt value and therefore may align better with clinical acumen. In this scenario, management based on the individual autoregulation-guided CPP could be a compromise between the aggressive CPP-oriented therapy promulgated by Rosner and colleagues
      • Rosner M.J.
      • Rosner S.D.
      • Johnson A.H.
      Cerebral perfusion pressure: management protocol and clinical results.
      and the more permissive Lund protocol.
      • Eker C.
      • Asgeirsson B.
      • Grände P.O.
      • Schalén W.
      • Nordström C.H.
      Improved outcome after severe head injury with a new therapy based on principles for brain volume regulation and preserved microcirculation.
      A recent nested randomised controlled study showed that keeping MAP above the individual LLA (using TCD-based mean flow index [Mx]) in cardiothoracic patients during cardiopulmonary bypass significantly reduced the incidence of postoperative delirium by 45%.
      • Brown C.H.
      • Neufeld K.J.
      • Tian J.
      • et al.
      Effect of targeting mean arterial pressure during cardiopulmonary bypass by monitoring cerebral autoregulation on postsurgical delirium among older patients: a nested randomized clinical trial.
      Fig 5
      Fig 5CPPopt determination with the ‘lower’ and ‘upper’ ends of regulation. (a) The U-shaped PRx–CPP curve showing the automated CPPopt. The PRx threshold is set at 0.3 for impaired autoregulation (white line). The intersection with the U-shaped curve results in upper and lower reactivity CPP (CPP LLR and ULR, respectively) values. (b) U-shaped PRx–CPP curve showing the automated CPPopt. The PRx threshold is set at 0.0 for impaired autoregulation (white line) leading to smaller CPP range between the upper and lower reactivity CPP (CPP LLR and ULR, respectively) values. ABP, arterial blood pressure; CPP, cerebral perfusion pressure; CPPopt, cerebral perfusion pressure optimum; ICP, intracranial pressure; PRx, pressure reactivity index (correlation between slow waves of ICP and ABP).
      As described above, the feasibility of a 4-hourly updated CPP target is currently tested in the prospective COGiTATE study. Irrespective of the published results, one might argue that a faster and continuous adaption of the CPP target (within preset safety ranges) might be more suitable and beneficial. This practise will probably prove to be very labour intensive and could trigger speculations about the use of an automated system which allows continuous delivery of drugs (e.g. noradrenaline) in a closed-loop system in a neurocritical care setting. However, it is important to be cautious about such approaches, because the time constants for changing autoregulation may be more rapid than the pharmacokinetic and pharmacodynamics temporal precision in which we can stabilise the MAP. Furthermore, our increasing understanding of autonomic influences on cerebral autoregulation may mean that catecholamines (and potentially, other vasoactive drugs) may have independent (and as yet poorly understood) direct effects on autoregulation. A better understanding of the biology of dysautoregulation, however, may allow us to use interventions that reduce its incidence and severity, and thus reduce reliance on manipulation of systemic physiology as our sole therapeutic target.

       Individual intracranial pressure thresholds

      Aside from personalised CPP targets, the concept of individual ICP thresholds has emerged utilising continuously monitoring cerebrovascular reactivity, mainly PRx. Retrospective literature suggests the tolerance for derangements in ICP and CPP is directly impacted by autoregulatory status, with dose response (i.e. outcome) heat map patterns seen in adult TBI populations which support a higher tolerance for ICP elevations when autoregulation is preserved.
      • Güiza F.
      • Depreitere B.
      • Piper I.
      • et al.
      Visualizing the pressure and time burden of intracranial hypertension in adult and paediatric traumatic brain injury.
      Furthermore, although the literature remains in its infancy, two studies to date have displayed a stronger association between time spent above individual ICP threshold, compared with BTF guideline based ICP thresholds.
      • Lazaridis C.
      • DeSantis S.M.
      • Smielewski P.
      • et al.
      Patient-specific thresholds of intracranial pressure in severe traumatic brain injury.
      ,
      • Zeiler F.A.
      • Ercole A.
      • Cabeleira M.
      • et al.
      Patient-specific ICP epidemiologic thresholds in adult traumatic brain injury: a CENTER-TBI validation study.
      The first study was a retrospective single-centre evaluation of manually determined individual ICP thresholds.
      • Lazaridis C.
      • DeSantis S.M.
      • Smielewski P.
      • et al.
      Patient-specific thresholds of intracranial pressure in severe traumatic brain injury.
      This study explored the relationship between PRx and ICP, with the individual ICP threshold determined by direct visual inspection of the error bar plots where PRx becomes consistently higher than +0.20. The ICP value after which PRx remains higher than +0.20 for all higher ICP values is deemed the individual ICP threshold. The results of this analysis demonstrated that the dose above individual ICP threshold displayed the highest discriminatory value for dichotomised outcome prediction (AUC=0.81; 95% confidence interval [CI], 0.74–0.87) over both the dose of ICP above a fixed threshold of 20 and 25 mm Hg (AUC=0.75; 95% CI, 0.68–0.81 and AUC=0.77; 95% CI, 0.70–0.83, respectively).
      The second study was a recent validation of data from the prospective multi-centre CENTER-TBI High Resolution ICU Sub-Study, in which a semi-automated algorithmic detection of the individual ICP threshold was developed, using the same criteria from the manual threshold study.
      • Zeiler F.A.
      • Ercole A.
      • Cabeleira M.
      • et al.
      Patient-specific ICP epidemiologic thresholds in adult traumatic brain injury: a CENTER-TBI validation study.
      This study used automated detection of the intersection between the locally weighted scatterplot smoothing (LOWESS) function of the PRx vs ICP relationship, and the line PRx=+0.20. Visual verification for each patient was conducted, making it semi-automatically. This study confirmed that approximately two-thirds of patients have an identifiable individual ICP threshold, whereas the mean hourly dose spent above individual ICP threshold displayed higher AUC (0.678, P=0.029) for outcome compared with dose of ICP of 20 or 22 mm Hg (AUC=0.509, P=0.03 and AUC=0.492, P=0.035, respectively). This effect was maintained with correction for baseline admission characteristics.
      Despite these results, the application of individual ICP thresholds is unclear and requires further validation and improvement of automated detection algorithms. Furthermore, such thresholds have only been studied using the entire ICU recording period, leaving them currently for post-ICU long-term prognostication.
      • Güiza F.
      • Depreitere B.
      • Piper I.
      • et al.
      Visualizing the pressure and time burden of intracranial hypertension in adult and paediatric traumatic brain injury.
      ,
      • Lazaridis C.
      • DeSantis S.M.
      • Smielewski P.
      • et al.
      Patient-specific thresholds of intracranial pressure in severe traumatic brain injury.
      ,
      • Zeiler F.A.
      • Ercole A.
      • Cabeleira M.
      • et al.
      Patient-specific ICP epidemiologic thresholds in adult traumatic brain injury: a CENTER-TBI validation study.
      If such thresholds are to be used clinically, moving window calculations will have to be developed, similar to CPPopt, allowing for continuously updating individual ICP threshold targets.

       Development of therapeutic targets for impaired cerebrovascular reactivity

      Our current treatment strategy for impaired cerebrovascular reactivity in adult moderate/severe TBI revolves around finding the ‘optimal’ CPP for which cerebrovascular reactivity indices indicated ‘intact’ autoregulation. However, there exists the need for therapies directed at reversing and preventing impaired autoregulation. As such, future studies on cerebrovascular reactivity in TBI will need to incorporate information from various sources, including those from the CNS systemic variables. Through using combinations of invasive/noninvasive MMM,
      • Le Roux P.
      • Menon D.K.
      • Citerio G.
      • et al.
      The International Multidisciplinary Consensus Conference on Multimodality Monitoring in Neurocritical Care: evidentiary tables: a statement for healthcare professionals from the neurocritical care society and the European society of intensive care medicine.
      ,
      • Czosnyka M.
      • Miller C.
      Participants in the international multidisciplinary consensus conference on multimodality monitoring. Monitoring of cerebral autoregulation.
      ,
      • Hutchinson P.J.
      • Jalloh I.
      • Helmy A.
      • et al.
      Consensus statement from the 2014 International microdialysis forum.
      both during the acute ICU and long-term follow-up phases of care, the relationship between continuously measured cerebrovascular reactivity and other important cerebral physiologic metrics can be uncovered and transformed into therapeutic targets. In the upcoming years, the link between continuously measured PbtO2, TD-CBF, ICP, CPP, cortical EEG, and cerebral metabolism, as assessed through cerebral microdialysis, may provide important insights into the relationships between cerebrovascular reactivity, CBF, BBB integrity and oxygen diffusion, autonomic response, CSD, and aerobic metabolism/mitochondrial function. In addition, systemic impairments associated with ventilation (e.g. Paco2) and cardiac function are likely to influence cerebrovascular reactivity and might lead to targeted intervention studies.
      Furthermore, integrating this high-frequency information with serum, microdialysis protein biomarkers of inflammation, or both, BBB integrity, and vascular function, may provide important insights into potential molecular pathways involved in impaired cerebrovascular reactivity and other cerebral physiologic dysfunction seen after moderate or severe TBI. In addition, including individual patient genome-wide association data may also uncover particular single nucleotide polymorphisms involved in CBF regulation and control during both the healthy and brain injured state, providing further information on potential molecular pathways driving autoregulatory dysfunction.
      • Zeiler F.A.
      • Thelin E.P.
      • Donnelly J.
      • et al.
      Genetic drivers of cerebral blood flow dysfunction in TBI: a speculative synthesis.
      ,
      • Zeiler F.A.
      • McFadyen C.
      • Newcombe V.
      • et al.
      Genetic influences on patient oriented outcomes in TBI: a living systematic review of non-APOE single nucleotide polymorphisms.
      Through combining all of these complex data, one may be able to determine individual therapeutic targets for impaired cerebrovascular reactivity in adult TBI, and develop therapies directed at prevention and treatment, reducing mortality in TBI. In addition, incorporating noninvasive NIRS or TCD based continuous cerebrovascular reactivity monitoring during follow-up clinic visits, combined with the complex physiologic and biological data obtained during the acute phase of care, we may be able to highlight the association between long-term clinical phenotype and persistent impairment of cerebrovascular reactivity. With knowledge of individual pathways involved in CBF control, gleamed from the acute phase data, persistent symptomatology related to cerebrovascular dysfunction may then be amendable to personalised therapeutics, with the goal of reducing long-term morbidity.

      Conclusions

      Over the previous decades, continuous cerebrovascular reactivity monitoring in adult critically ill TBI patients has emerged as an important physiologic metric, with strong links to global prognosis. Despite a lack of effective proven treatments directed at impaired cerebrovascular reactivity in TBI, continuous monitoring of this cerebral physiologic mechanism has led to important advancements in bedside care, with the availability of personalised CPP targets. Future research in cerebrovascular reactivity in adult TBI will revolve around improving personalised physiologic targets for ICU care, while exploring potential drivers of impaired vascular reactivity. The hope is that through integration of cerebral MMM, protein, imaging, and genetic biomarkers, the molecular mechanisms involved in cerebrovascular dysfunction after TBI will be uncovered, leading to therapies directed at prevention and new treatments in the acute phase.

      Authors' contributions

      Study concept, design, research, figure/artwork creation: FAZ, MA
      Writing paper: all authors
      Revising paper: AE, MC, PS, GH
      Discussion: AE, MC, PS, GH, PJH, DKM

      Declaration of interest

      PS and MC have financial interests in a part of licencing fee for ICM+ software (Cambridge Enterprise Ltd, UK). DKM has consultancy agreements and/or research collaborations with GlaxoSmithKline, Ornim Medical, Shire Medical, Calico, Pfizer, Pressura, Glide Pharma, and NeuroTraumaSciences.

      Funding

      University of Manitoba Thorlakson Chair for Surgical Research Establishment Grant, University of Manitoba VPRI Research Investment Fund (RIF) , Winnipeg Health Sciences Centre Foundation , and the University of Manitoba Rudy Falk Clinician–Scientist Professorship (to FAZ). NIHR (Research Professorship, Cambridge BRC and Global Health Research Group on Neurotrauma) (to PJH). National Institute for Healthcare Research (NIHR, UK) through the Acute Brain Injury and Repair theme of the Cambridge NIHR Biomedical Research Centre and a European Union Framework Program 7 grant ( CENTER-TBI ; Grant Agreement No. 602150 ).

      Appendix A. Supplementary data

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